Restricted population. The large majority of controlled vaccine trials are geared toward investigating childhood vaccines. Adverse effects in children may not be generalizable to adults.

Progress in vaccine technology. Earlier vaccines against a particular infectious agent that have been subjected to considerable animal and human study may be substantially different from vaccines currently in use against the same infectious agent. Thus, even careful and extensive earlier studies may not be generalizable to current experience.

Difficulties in Detecting Adverse Events Due to Vaccinations in Animals

Focus on Vaccine Efficacy

Most animal studies focus on the efficacy of the vaccine and do not examine adverse effects. Further, adverse effects that produce symptoms, rather than objectively measurable pathology, are difficult or impossible to study in animals (some studies use animal behavior to infer animal symptoms such as fatigue). The lack of data on adverse events in animal studies can indicate that no adverse events occurred, that adverse events were not monitored, or that adverse events were not sufficiently severe to warrant termination of the experiment. Additionally, most animal studies are concerned with monitoring immediate toxicity to the administration of the vaccine. Animals are most often followed for short periods of time (i.e., weeks to months), and the long-term effects of vaccination are not considered.

Possibility of Immune Stimulation

Studies in animals have generally not considered the mechanism responsible for adverse health effects. In some cases, adverse effects of the vaccination could be due to the toxicity of the antigen in the vaccine, the preservatives or contaminants in the vaccine, or the vaccine adjuvant.2 Adverse effects may also result from the intended goal of immunization (i.e., stimulation of the immune system). Immune stimulation may result in a state of immune enhancement, hypersensitivity, or an immune-mediated pathological response. The pathological immune response may be directed toward the antigens administered in the vaccine or to self-antigens (i.e., autoimmunity). Immune-mediated tissue damage requires an initial exposure to the antigen to sensitize the animal. The symptoms of immune-mediated tissue damage may occur on subsequent exposures.

A discussion of the immunological reactions that can cause disease has been included in a previous IOM (1994) report and is summarized only briefly here. Classically, such immune-mediated pathology is divided into Types I–IV hyper-

2

An adjuvant is a substance that is used to increase the immune response to specific vaccine components.

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